During the past decade the genetics of development and cancer have converged in the identification of signaling pathways that control embryo patterning and, when aberrantly regulated, lead to cancer. Typically, tumors form in tissues in which these pathways normally operate. Tumors arise due to oncogenic mutations in components of these pathways that lead to ligand-independent constitutive activity. A classic example is the canonical Wnt signaling pathway, an essential developmental pathway that is disrupted in several kinds of tumor. Mouse Wnt1 is a prototypical oncogene first identified when it was shown that activation of Wnt1 by integration of Mouse Mammary Tumor Virus led to cancer of the mammary gland in mice. The transcriptional coactivator beta-catenin is the primary effector of the canonical Wnt signaling pathway. Mutations in several components of the Wnt/beta-catenin pathway have identified both oncogenes and tumor suppressors in this pathway that lead, in particular, to colorectal cancer. Recently, we have shown that embryos lacking Wnt5a display severe growth defects in the developing gastrointestinal tract. We are currently examining the mechanisms underlying this phenotype. We are also assessing potential genetic interactions between Wnt5a and current mouse models of colorectal cancer. In collaboration with Jeff Rubin (NCI-Bethesda), we have characterized the expression of the secreted Wnt antagonist sfrp1 during mouse embryogenesis. Sfrp1 is highly expressed in the developing embryo, including the colon and small intestine. Given that sfrps are negative regulators of the Wnt pathway and that aberrant activation of the Wnt pathway leads to cancers of the gut, we are interested in determining whether sfrps have tumor suppressor activity. To test for tumor suppressor activity genetically, we have generated loss-of-function alleles of sfrp1. Genetic interactions between animals lacking sfrp and mouse models of colorectal cancer are currently being examined.